The Intracellular Loop of the Glycine Receptor: It’s not all about the Size

Abstract

The family of Cys-loop receptors (CLRs) shares a high degree of homology and sequence identity. The overall structural elements are highly conserved with a large extracellular domain (ECD) harboring an α-helix and 10 β-sheets. Following the ECD, four transmembrane domains (TMD) are connected by intracellular and extracellular loop structures. Except the TM3–4 loop, their length comprises 7–14 residues. The TM3–4 loop forms the largest part of the intracellular domain (ICD) and exhibits the most variable region between all CLRs. The ICD is defined by the TM3–4 loop together with the TM1–2 loop preceding the ion channel pore. During the last decade, crystallization approaches were successful for some members of the CLR family. To allow crystallization, the intracellular loop was in most structures replaced by a short linker present in prokaryotic CLRs. Therefore, no structural information about the large TM3–4 loop of CLRs including the glycine receptors (GlyRs) is available except for some basic stretches close to TM3 and TM4. The intracellular loop has been intensively studied with regard to functional aspects including desensitization, modulation of channel physiology by pharmacological substances, posttranslational modifications, and motifs important for trafficking. Furthermore, the ICD interacts with scaffold proteins enabling inhibitory synapse formation. This review focuses on attempts to define structural and functional elements within the ICD of GlyRs discussed with the background of protein-protein interactions and functional channel formation in the absence of the TM3–4 loop.

The dual‐gate model for pentameric ligand‐gated ion channels activation and desensitization

“…). Further work showed the involvement of intracellular M3–M4 linker mutation or splice variant in desensitization (Papke & Grosman, ; Langlhofer & Villmann, ).…”

“…The M2 segments line the pore, allowing the selective flow of permeant ions in the open conformation of the channel (Giraudat et al 1986;Imoto et al 1988;Leonard et al 1988). Amidst this well-ordered modular architecture, the M3-M4 loop is involved in the trafficking of the receptors to the plasma membrane, their anchoring at the synapse, and their modulation by intracellular interactions and phosphorylation (Smart & Paoletti, 2012;Langlhofer & Villmann, 2016). While the central portion of this cytoplasmic loop is a highly variable and flexible region, the post-M3 and pre-M4 regions fold into α-helices called MX and MA, respectively (Hassaine et al 2014).…”

Mechanisms of activation and desensitization of full-length glycine receptor in membranes

“…The ECD houses neurotransmitter binding pocket and the TMD governs the machinery for selective ion permeation. The ICD is important for receptor trafficking, synaptic clustering and is a central site for posttranslational modifications and regulation by endogenous and exogenous modulators [11][12][13][14][15] .…”

The role of charged residues in independent glycine receptor folding domains for intermolecular interactions and ion channel function

“…). The TM3‐4 loop acts as a site for post‐translational modifications and modulation of desensitization kinetics (Langlhofer and Villmann ). Lack of large portions of the TM3‐4 loop sequences did, however, not result in non‐functionality arguing that the small residual basic subdomains close to TM3 and 4 are sufficient to enable functional ion channel formation.…”